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Cholinergic drugs.pptx
- 1. CHOLINERGIC DRUGS PRESENTER : DR. KRUSHAL PABARI JR-1, MD PHARMACOLOGY 1
- 2. Topics to be covered Muscarinic Receptors Cholinergic agonists Mushroom Poisoning Anticholinesterases Myasthenia Gravis Organophosphate Poisoning 2
- 3. Autonomic nervous System Parasympathetic Nervous System Cranio-sacral outflow Sympathetic Nervous System Thoraco-lumbar outflow 3
- 4. Organs supplied by parasympathetic nervous system 4
- 5. Organs supplied by sympathetic nervous system 5
- 6. 6 Ganglion : A collection of neuronal bodies. - accepts action potential, regenerates and propagates to organ of interest. - located closer to organs in Parasympathetic nervous system - located closer to vertebra in Sympathetic nervous system ●In Parasympathetic Nervous system : preganglionic fibres are longer postganglionic fibres ●In Sympathetic Nervous system : postganglionic fibres are longer preganglionic fibres
- 7. MECHANISHM OF PROPOGATION OF ACTION POTENTIAL. - Action Potential traverses along 1st Neuron Depolarises Presynaptic Membrane and opens Ca2+ channel Ca2+ ions move in and cause contraction of proteins on vesicles Vesicales move foreward, fuse with Presynaptic membrane Exocytosis of Neurotransmitter = Ach Acts on Post synaptic receptor (Nicotinic) Na+ ion channels open followed by Influx of Na+ AP generated 7
- 8. 8 Synthesis of Acetylcholine (Ach)
- 9. 9
- 10. Muscarinic Receptor Location & Function Target Receptor Response Eye Sphincter Ciliary muscle M3 M3 Contraction—miosis Contraction—accommodation for near vision Heart SA node AV node M2 M2 ↓Heart rate (HR)—negative chronotropy ↓ Conduction velocity—negative dromotropy No effects on ventricles, Purkinje system Lungs Bronchioles Glands M3 M3 Contraction—bronchospasm ↑ Secretion GI tract Stomach Glands Intestine M3 M1 M3 ↑ Motility—cramps ↑ Secretion Contraction—diarrhea, involuntary defecation 10
- 11. Bladder M3 Contraction (detrusor), relaxation (trigone/sphincter), voiding, urinary incontinence Sphincters M3 Relaxation, except lower esophageal, which contracts Glands M3 ↑ Secretion—sweat (thermoregulatory), salivation, and lacrimation Blood vessels (endothelium) M3 Dilation (via NO/endothelium-derived relaxing factor)—no innervation, no effects of indirect agonists 11
- 12. Cholinergic Agonists Choline esters Acetyl choline Methacholine Carbachol Bethanechol Alkaloids Muscarine Pilocarpine Arecoline 12
- 13. Bethanechol Carbachol Methcholine Musarinic effect M3 > M2 M1/ M3 > M2 M2 > M1/M3 Nicotinic effect ---- Maximum Moderate Uses • Neurogenic Bladder • Postoperative/ postpartum nonobstructive urinary retention • Miotic in Occular Surgeries • Treatment of Glaucoma • Diagnosis of Bronchial Asthama. • Bronchial Challenge test. 13
- 14. 14 PILOCARPINE History- Obtained from leaves of Pilocarpus microphyllus Effect- Eyes • Miosis • Ciliary muscle contraction • Fall in the intraocular tension USES • Closed angle Glaucoma • Sjogren syndrome Glands • Increase in Sweat and salivary secretions Adverse effects- Accomodation Spasm leading to headache and retinal detatchment Dose: In Rx of Sjogren Syndrome- 5-10 mg thrice daily. Contrainidcations- Asthama COPD GI/ Urinary Obstruction
- 15. Muscarine type/ early type (30-60 minutes) Hallucinogenic type Phalloidin type (late onset type) Toxic agent Inocybe in Inocyte species Muscimol present in A. muscaria Psilocybine in Psilocybe mexicana Peptide toxins found in Amanita phalloides, Galerina species. Effect Muscarinic- salivation, bronchospasm, nausea, vomiting, abdominal pain, bradychardia and hypotension. • Neurological symptoms like irritability, ataxia, delirium, sedation • Muscimol, Ibotenic acid, isoxazole derivative- Hallucinations • Most serious type. >90% fatalities. • Late onset, patient may be symptom free upto 24 hours except diarrhoea and abdominal cramp. • Hepatic & renal failure. Treatment Atropine 2mg i.v. and 1-2 mg repeated every half an hour till resolves No specific treatment. Atropine is C/I Supportive measures. 15
- 17. Acetylcholinesterase Butyrylcholinesterase /Pseudocholinesterase (BuChE) Distribution All cholinergic sites, erythrocytes, Brain (Grey matter) Plasma, liver, skin, brain(white matter)and gastrointestinal smooth muscles Substrate hydrolysed Acetylcholine Butyrylcholine Hydrolysed (ultra fast) Not hydrolysed Hydrolysed (slow) Hydrolysed Inhibition Relatively more sensitive to physostigmine Relatively most sensitive to Organophosphates Function Degrades acetylcholine Degrades exogenous esters 17
- 18. 18 • Anionic site- binds with choline moiety of ACh • Esteratic site- binds with acetyl moiety of ACh • Hydrolysis of Ach occurs by transferring acetyl group to Serine hydroxyl group, leaving behind free choline. • Acetylated enzyme reacts freely with water to release acetic acid and liberate free enzyme.
- 19. 19 • Carbamates + Esteratic site --- Enzyme is Carbamylated releasing choline, BUT carbamylated enzyme reacts slowly with water and enzyme is freed slowly. • Half life of reactivation of carbamylated enzyme Is about 30 minutes • Edrophonium + anionic site of enzyme AChE and the ionic bond is readily reversible and thus, it has very short action, about 10 minutes
- 20. Parameter Physostigmine Neostigmine and other quaternary compounds Source Physostigma venenosum ( dried ripe seeds of Calabar beans) Synthetic Oral Absorption Good Poor Penetration to cornea Good Poor Penetration to CNS Good Poor Additional direct action on cholinergic receptors Abesnt Present 20
- 21. Parameter Physostigmine Neostigmine and other quaternary compounds Predominant effect Parasympathetic effectors NM Junction, GIT,CVS and Eye. Preferred Clinical use • Glaucoma (0.25-0.5%) • Belladona Poisoning Dose- 2 mg sc/i.v. and repeated initially every 15-20 minutes and later every 2 hours. • Diagnosis & treatment of Myasthenia Gravis. • Non depolarizing muscle relaxant (NDMR) reversal • Cobra bite • Bladder atony 21
- 22. long acting drug as compared to Neostigmine, though less potent. Onset is delayed and peak effect occurs after 2 hours. Better compliance than Neostigmine Safe in Pregnancy and lactation Dose: 60-120 mg TDS 22 Pyridostigmine.
- 23. Ultra short acting ( ~10 minutes) as it combines with anionic site of AchE and forms ionic bond which is readily reversible Has mainly peripheral actions. Drug of choice in Myasthenia Gravis Used to differentiate between myasthenic crisis and cholinergic crisis Edrophonium test: Premedication with Atropine. If Symptoms improve --- Myasthenia Gravis If Symptoms worsen --- Cholinergic crisis 23 Edrophonium
- 24. Highly lipid soluble, cross BBB Inhibit AChE in CNS and thus can be used for trratment of Alzhimer’s disease. It has a long half life, and thus can be used only once a day. Can cause hepatoxicity. Delays the progress of disease upto one year. Dose: 5 mg OD at Bed time (maximum 10 mg OD) 24 Donepezil
- 25. Autoimmune disorder, occurring due to development of antibodies directed to Nicotinic receptors at muscle end plate. Number of free Nm cholinoceptors may be reduced to 1/3rd of normal Symptoms- Weakness and easy fatigability on repeated activity with recovery after rest. Treatment- Neostigmine- increases the availability of Ach from prejunctional endings to accumulate and act on receptors over a large area. Dose: 15 mg orally 6 hourly Prednisolone 30-60 mg/day produces remission in 80% of advanced cases. After tapering the dose, 10 mg daily or alternate days. Plasmaphersis. 25 Myasthenia gravis
- 26. Condition Drugs used Glaucoma Pilocarpine, Physostigmine Testing of Myasthenia gravis Edrophonium Treatment of Myasthenia gravis Neostigmine & Pyridostigmine Cobra bite Edrophonium ( prevents respiratory paralysis) Atropine Poisoning Physostigmine TCA, Phenothiazines overdose Physostigmine Post operative paralytic ileus Neostigmine 26
- 27. Organophosphate Poisoning Caused by irreversible cholinesterase inhibitors Route of entry- Eye, skin, respiratory system and GI tract they are- Organophoshate insecticides (malathion, parathion) or nerve gases (sarin, tabun, soman) They cause excessive cholinergic stimulation (muscarinic) and neuromuscular blockade producing symptoms of - increased salivation, rhinorrhoea and sweating, excessive bronchial secretion and difficulty in respiration due to Bronchoconstriction. - Miosis, vomiting, diarrhoea and abdominal pain - Muscle twitching begins with eyelids, tongue. 27
- 28. Peripheral neuromuscular blocking action and excessive bronchial secretion --- respiratory paralysis – Death. Cholinergic crisis occurs because the irreversible anticholinesterase poison binds to the enzyme acetylcholinesterase and inactivates it. Thus, acetylcholine remains in the cholinergic synapses causing excessive stimulation of muscarinic and nicotinic receptors. 28
- 29. Treatment of OP Poisoning GENERAL SUPPORTIVE MEASURES. Prevention of further exposure to poison. Decontamination of clothing Flushing poison from the skin and eyes Activated charcoal and lavage for GI ingestion 29
- 30. Specific Treatment. A. ATROPINE- Drug of choice. Dose- 2mg i.v. to start with and same dose repeated until full atropinisation is achieved. Atropinisation is assessed by degree of dilatation of pupil and pulse count, i.e. increased pulse rate should be seen. Tachycardia upto 120 beats per minute is allowed. 30
- 31. B. Cholinesterase reactivators. Phosphorylated cholinesterase enzyme does not react with water at all and therefore, action is irreversible. So, if compounds possessing highly reactive hydroxyl group (OH) is used, cholinesterase enzyme is reactivated very fast. OXIMES- Pralidoxime, obidoxime, diacetyl monoxime. Pralidoxime Dose- administered slow IV infusion for 15-30 minutes. Adults- 1-2 gm Children- 20-40 mg/kg Pralidoxime should be administered as early as possible. 31
- 32. 32 Pralidoxime combines with anionic site of the phosphorylated enzyme, and comes in close proximity with phosphorylated Esteratic site. Oxime end reacts with Phosphorous atom of Organophosphate at Esteratic site and enzyme is reactivated. Oximes not useful in treatment of Carbamate poisoning.
- 33. References 1. Wessler I, Kilbinger H, Bittinger F, Unger R, Kirkpatrick CJ. The non- neuronal cholinergic system in humans: Expression, function and pathophysiology. Life Sciences. 2003;72:2055–2061 2. Goodman & Gilman’s The Pharmacological basis of therapeutics 3. SK Srivastava Rohan Srivastava, Pharmacology for MBBS 4. Essentials of Medical Pharmacology, KD Tripathi. 33
- 34. Thank You 34